Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/24—Condensed ring systems having three or more rings
  • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to new pyrido-pyrido-pyrrolo[3,2-g]pyrrolo[3,4-e]indole and pyrido-pyrrolo[2,3-a]pyrrolo[3,4-c]carbazole compounds, to a process for their preparation and to pharmaceutical compositions containing them.
• Anti-cancer therapeutic requirements call for the constant development of new antiproliferative agents with the aim of obtaining medicaments that are simultaneously more active and better tolerated.
• the compounds of the present invention especially have anti-tumour properties, making them of use in the treatment of cancers.
• Patent Applications WO95/07910 and WO96/04906 describe indole compounds, claiming them, on the one hand, for their antiviral activity and, on the other hand, for the treatment and prevention of restenosis.
• Patent Applications WO00/47583, WO97/21677 and WO96/11933 describe cyclopenta[g]pyrrolo[3,4-e]indole compounds fused, by the indole moiety and the cyclopentene moiety of the compounds, to an aromatic or non-aromatic cyclic system, and optionally containing hetero atoms. Those compounds have pharmacological activities making them especially useful in the treatment of cancerous cells.
• the compounds of the present Application differ greatly from those described in the prior art and possess particular pharmacological properties and, especially, surprising in vivo and in vitro activity with respect to various cell lines, making them of use in the treatment of cancers.
• hydrochloric acid hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fuimaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid etc.
• Preferred compounds of the invention are those wherein X and Y, together with the carbon atom carrying them, form a carbonyl group and X 1 and Y 1 , together with the carbon atom carrying them, form a carbonyl group.
• preferred compounds of the invention are compounds of formula (I) that correspond in particular to formula (IA): wherein R 1 , R 2 , R 3 , R 5 , R a , R b , R c , R d , W 1 and W 2 are as defined for formula (I).
• preferred compounds of the invention are compounds of formula (I) that correspond in particular to formula (IC): wherein R 1 , R 2 , R 3 , R 5 , R a , R b , R c and R d are as defined for formula (I).
• preferred compounds of the invention are compounds of formula (I) that correspond in particular to formula (ID): wherein R 1 , R 2 , R 3 , R 5 , R a , R b , R c and R d are as defined for formula (I).
• preferred compounds of the invention are compounds of formula (IE): wherein R 1 , R 2 , R 3 , R 5 , R b , R c , R d , n, W 1 and W 2 are as defined for formula (I).
• preferred compounds of the invention are compounds of formula (IF): wherein R 1 , R 2 , R 3 , R 5 , R a , R b , R c , R d , W 1 and W 2 are as defined for formula (I).
• preferred compounds of the invention are compounds of formnula (IG): wherein R 1 , R 2 , R 3 , R 5 , R a , R b , R c and R d are as defined for formula (I).
• preferred compounds of the invention are compounds of formula (IH): wherein R 1 , R 2 , R 3 ,R 5 , R a , R b , R d are as defined for formula (I).
• preferred compounds of the invention are compounds of formula (IJ): wherein R 1 , R 2 , R 3 , R 5 , R a , R b , R c and R d are as defined for formula (I).
• the pyridine ring that is preferred according to the invention is the unsubstituted ring.
• the group R4 that is preferred according to the invention is the glucopyranosyl group of formula:
• the group R 2 that is preferred according to the invention is the hydrogen atom.
• the groups R 1 that are preferred according to the invention are the hydrogen atom, halogen atoms and the nitro group.
• Preferred compounds according to the invention are:
• the present invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material a compound of formula (II): wherein BOM represents a benzyloxymethyl group and X, Y, X 1 and Y 1 are as defined for formula (I), which compound of formula (II) is treated with an alkylmagnesium halide in the presence of a compound of formula (III): wherein W 1 is as defined for formula (I), to yield the compound of formula (IV): wherein X, Y, X 1 , Y 1 , BOM and W 1 are as defined hereinbefore, which compound of formula (IV) is reacted with benzenesulphonyl chloride in the presence of sodium hydride to yield the compound of formula (V): wherein BOM, X, Y, X 1 , Y 1 and W 1 are as defined hereinbefore, which compound of formula (V) is reacted, in the presence of lithium he
• the compound of formula (IX) is useful as a synthesis intermediate in obtaining compounds of formula (I).
• the compounds of formula (I) have especially valuable anti-tumour properties.
• the characteristic properties of these compounds allow them to be used therapeutically as anti-tumour agents.
• the present invention relates also to pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (I), an optical isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
• compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragees, sublingual tablets, soft gelatin capsules, hard gelatin capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops etc.
• the pharmaceutical compositions comprising the said compounds of formula (I) as active ingredient are accordingly especially useful in the treatment of cancers.
• the useful dosage varies according to the age and weight of the patient, the route of administration, the nature and severity of the disorder and the administration of any associated treatments, and ranges from 1 mg to 500 mg per day in one or more administrations.
• the starting materials used are materials that are known or that are prepared according to known procedures.
• Step A 1-[(benzyloxy)methyl]-3-bromo-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione
• a solution of ethylmagnesium bromide is prepared, starting from magnesium (6.75 mmol) suspended in bromoethane (6.75 mmol) and dry tetrahydrofuran (5 ml). The solution is stirred at ambient temperature for 15 minutes and is then heated at 40° C. for 20 minutes. A solution of indole (6.75 mmol) in 40 ml of dry tetrahydrofuran is then added dropwise. After stirring for 1 hour at 40° C., the reaction mixture is cooled and then a solution of N-benzyloxymethyl-2,3-dibromomaleimide (3.38 mmol) in 40 ml of dry tetrahydrofuran is added dropwise.
• reaction mixture is stirred for 15 hours and is then hydrolysed with saturated aqueous ammonium chloride solution.
• the organic product is extracted with ethyl acetate, and the organic phases are then combined, dried over magnesium sulphate and filtered. After evaporating off the solvent and purifng the residue by chromatography on silica gel (cyclohexane/ethyl acetate: 4/1), the expected product is isolated.
• Step B 1-[(benzyloxy)methyl]-3-bromo-4-[1-(phenylsulphonyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione
• the organic product is extracted with ethyl acetate, and the organic phases are then combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered. After evaporating off the solvent and purifying the residue by chromatography on silica gel (cyclohexane/ethyl acetate: 85/15), the expected product is isolated.
• Step C 1-[(benzyloxy)methyl]-3-[1-(phenylsulphonyl)-1H-indol-3-yl]-4-(1H-pyrrolo[2, 3-b]pyrid-3-yl)-1H-pyrrole-2,5-dione
• Step A 1-[(benzyloxy)methyl]-3-bromo-4-(1H-pyrrolo[2,3-b]pyrid-3-yl)-1H-pyrrole-2,5-dione
• a solution of ethylmagnesium bromide is prepared, starting from magnesium (6.00 mmol) suspended in bromoethane (6.00 mmol) and dry tetrahydrofuran (2.5 ml). The solution is stirred at ambient temperature for 1 hour and then 7-azaindole (6.00 mmol), dissolved in 20 ml of anhydrous toluene, is added dropwise. After stirring at ambient temperature for 1 hour 30 minutes, a solution of N-benzyloxymethyl-2,3-dibromomaleimide (2.01 mmol) in 20 ml of anhydrous toluene is added dropwise.
• Step B 1-[(benzyloxy)methyl]-3-bromo-4-[1-(phenylsulphonyl)-1H-pyrrolo[2,3-b]-pyrid-3-yl]-1H-pyrrole-2,5-dione
• the product is obtained according to the procedure of Step B of Preparation A, using the product obtained in Step A above as substrate.
• Step C 1-[(benzyloxy)methyl]-3-(1H-indol-3-yl)-4-[1-(phenylsulphonyl)-1H-pyrrolo-[2,3-b]pyrid-3-yl]-1H-pyrrole-2,5-dione
• a solution of ethylmagnesium bromide is prepared, starting from magnesium (0.62 mmol) suspended in bromoethane (0.62 mmol) and dry tetrahydrofuran (0.4 ml). The solution is stirred at ambient temperature for 15 minutes and is then heated at 40° C. for 20 minutes. A solution of indole (0.65 mmol) in 3 ml of anhydrous toluene is then added dropwise. After stirring for 1 hour at 40° C., the reaction mixture is cooled and then a solution of the compound obtained in Step B (0.254 mmol) in 5 ml of anhydrous toluene is added dropwise.
• reaction mixture is stirred for 15 hours and is then hydrolysed with saturated aqueous ammonium chloride solution.
• the organic product is extracted with ethyl acetate, and the organic phases are then combined, dried over magnesium sulphate and filtered. After evaporating off the solvent and purifying the residue by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2), the expected product is isolated.
• the product is obtained according to the procedure of Step C of Preparation A, using the compound obtained in Step B of Preparation B as substrate.
• Step A 3-bromo-1-methyl-4-(1H-pyrrolo[2,3-b]pyrid-3-yl)-1H-pyrrole-2,5-dione
• a solution of ethylmagnesium bromide is prepared, starting from magnesium (12.7 mmol) suspended in bromoethane (12.7 mmol) and dry tetrahydrofuran (5 ml). The solution is stirred at ambient temperature for 1 hour and then 7-azaindole (12.7 mmol), dissolved in 40 ml of anhydrous toluene, is added dropwise. After stirring at ambient temperature for 1 hour 30 minutes, a solution of N-methyl-2,3-dibromomaleimide (3.53 mmol) in 40 ml of anhydrous toluene is added dropwise. After 20 minutes, 60 ml of dry dichloromethane are added; the reaction mixture is then stirred at 40° C.
• Step B 3-bromo-1-methyl-4-[1-(phenylsulphonyl)-1H-pyrrolo[2,3-b]pyrid-3-yl]-1H-pyrrole-2,5-dione
• the organic product is extracted with ethyl acetate, and the organic phases are then combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered. After evaporating off the solvent and purifying the residue by chromatography on silica gel (cyclohexane/ethyl acetate: 4/1), the expected product is isolated.
• Step C 1-methyl-3-[1-(phenylsulphonyl)-1H-pyrrolo[2,3-b]pyrid-3-yl]-4-(1H-pyrrolo[2,3-b]pyrid-3-yl)-1H-pyrrole-2,5-dione
• the product is obtained according to the procedure of Step C of Preparation A, using the product obtained in Step B above as substrate.
• reaction is stopped by the addition, at 0° C., of 50 ml of 0.3N hydrochloric acid solution.
• the reaction mixture is extracted with ethyl acetate, and the organic phases are washed with saturated NaCl solution, dried over MgSO 4 and then evaporated under reduced pressure.
• the desired product is precipitated using methanol.
• Step B tert-butyl 3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole-1-carboxylate
• Step C tert-butyl 3-[1-methyl-2,5-dioxo-4-(1H-pyrrolo[2,3-b]pyrid-3-yl)-2,5-dihydro-1H-pyrrol-3-yl]-1H-indole-1-carboxylate
• Step A 3-(1H-indol-3-yl)-4-[1-( ⁇ -D-glucopyranosyl)-1H-pyrrolo[2,3-b]pyrid-3-yl]-1H-furan-2,3-dione
• Step B 13-( ⁇ -D-glucopyranosyl)-12,13-dihydrofuro[3,4-c]pyrido[3′,2′:4,5]pyrrolo-[2,3-a]carbazole-5,7-dione
• the product is obtained according to the procedure of Example 1c, using the compound of Step A above as substrate.
• the product is obtained according to the procedure of Step C of Preparation B, using the product obtained in Step B of Preparation D as substrate.
• the ⁇ -glycosylated compound is obtained in the form of yellow crystals and the ⁇ -glycosylated compound is obtained in admixture with triphenylphosphine oxide.
• Example 1c To a solution of the compound of Example 1c (0.067 mmol) in 3 ml of dry methanol and 1 ml of dry ethyl acetate there is added 10% palladium-on-carbon (18.1 mg). The reaction mixture is degassed twice and is then stirred at ambient temperature under a hydrogen atmosphere (1 bar). After 24 hours, more 10% palladium-on-carbon (21.0 mg) is added. The reaction mixture is degassed again and then held under a hydrogen atmosphere for 48 hours. The mixture is filtered over Celite, and the solid is then washed with methanol and ethyl acetate. After evaporating off the solvents and purifying the residue by chromatography on silica gel (cyclohexane/ethyl acetate: 65/35), the expected product is isolated.
• Example 2 To a solution of the compound of Example 2 (0.030 mmol), dissolved in 9.4 ml of methanol, there is added 28% aqueous ammonium hydroxide solution (8 ml). The mixture is stirred for 19 hours at ambient temperature. After evaporating off the solvents, the residue is taken up in a mixture of water/ethyl acetate and is then filtered over a frit. The crystals are successively washed with ethyl acetate and then with methanol. The expected compound is obtained in the form of yellow crystals.
• the residue obtained is dissolved in 8 ml of methanol, and then 28% aqueous ammonium hydroxide solution (9 ml) is added. The mixture is stirred for 22 hours at ambient temperature, protected from light. After evaporating off the solvents, the residue is taken up in a water/ethyl acetate mixture and is then filtered over a frit. The crystals are washed with ethyl acetate, allowing the expected product to be obtained.
• the mixture is stirred for 16 hours at ambient temperature. After evaporating off the solvents, the residue is taken up in a water/ethyl acetate mixture and is then filtered over a frit. The crystals are washed with ethyl acetate, allowing the expected product to be isolated.
• the product is obtained according to the procedure of Example 1b, using the compound of Example 7a as substrate.
• the product is obtained according to the procedure of Example 1c, using the compound of Example 7b as substrate.
• Example 7c To a solution of the compound of Example 7c (0.090 mmol) in 40 ml of dry methanol and 20 ml of dry ethyl acetate there is added 10% palladium-on-carbon (60 mg). The reaction mixture is degassed twice and is then stirred at ambient temperature under a hydrogen atmosphere (1 bar). After 17 hours, more 10% palladium-on-carbon (31 mg) is added. The reaction mixture is degassed again and is then held under a hydrogen atmosphere for 21 hours. The mixture is filtered over Celite, and the solid is then washed with methanol and with chloroform. After evaporating off the solvents and purifying the residue by chromatography on silica gel (cyclohexane/ethyl acetate: 1/1), the expected product is isolated.
• Example 8 To a solution of the compound of Example 8 (0.040 mmol), dissolved in 13 ml of methanol, there is added 28% aqueous ammonium hydroxide solution (9 ml). The mixture is stirred for 15 hours at ambient temperature. After evaporating off the solvents, the residue is taken up in a water/ethyl acetate mixture and is then filtered over a frit. The crystals are successively washed with ethyl acetate and then with methanol, allowing the expected product to be isolated.
• the products are obtained, after separation on silica gel, according to the procedure of Example 1a, using the compound of Preparation C as substrate.
• the product is obtained according to the procedure of Example 1b, using the compound of Example 10a as substrate.
• the product is obtained according to the procedure of Example 1c, using the compound of Example 10b as substrate.
• Example 10c To a solution of the compound of Example 10c (0.090 mmol) in 4.5 ml of dry methanol and 1.5 ml of dry ethyl acetate there is added 10% palladium-on-carbon (84.0 mg). The reaction mixture is degassed twice and is then stirred at ambient temperature under a hydrogen atmosphere (1 bar) for 24 hours. After 24 hours, more 10% palladium-on-carbon (42.0 mg) is added. The reaction mixture is degassed again and is then held under a hydrogen atmosphere for 24 hours. The mixture is filtered over Celite, and the solid is washed with methanol and with chloroform. After evaporating off the solvents and purifying the residue by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2), the expected product is isolated.
• Example 11 To a solution of the compound of Example 11 (0.053 mmol), dissolved in 15 ml of methanol, there is added 28% aqueous ammonium hydroxide solution (13 ml). The mixture is stirred at 40° C. for 21 hours. After evaporating off the solvents, the residue is taken up in a water/ethyl acetate mixture and is then filtered over a frit. The crystals are successively washed with ethyl acetate and then with methanol, allowing the expected product to be isolated.
• Example 10c To a solution of the compound of Example 10c (0.054 mmol), dissolved in 13 ml of methanol, there is added 28% aqueous ammonium hydroxide solution (13 ml). The mixture is stirred at 40° C. for 19 hours. After evaporating off the solvents, the residue is taken up in a water/ethyl acetate mixture and is then filtered over a frit. The crystals are successively washed with ethyl acetate and then with methanol, allowing the expected product to be isolated.
• the product is obtained, after chromatography on silica gel, according to the procedure of Example 1a, using the compound of Preparation D as substrate.
• Example 14b To a solution of the compound of Example 14b (0.054 mmol), dissolved in 14 ml of methanol, there is added 28% aqueous ammonium hydroxide solution (10 ml). The reaction mixture is stirred for 26 hours at ambient temperature. After evaporating off the solvents, the residue is purified by chromatography on silica gel (ethyl acetate/methanol: 9/1), allowing the expected product to be isolated.
• the product is obtained according to the procedure of Example 1c, using the compound of Example 14b as substrate.
• Example 14c To a solution of the compound of Example 14c (0.066 mmol), dissolved in 40 ml of methanol, there is added 28% aqueous ammonium hydroxide solution (28 ml). The mixture is stirred for 26 hours at 55° C. After evaporating off the solvents, the residue is taken up in a water/ethyl acetate mixture and is then filtered over a frit. The crystals are successively washed with ethyl acetate and then with methanol, allowing the expected product to be isolated.
• Example 16a The compound of Example 16a (0.114 mmol) is dissolved in 20 ml of formic acid. After stirring for 24 hours at ambient temperature, the solution is neutralised by adding, dropwise, triethylamine, and then saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and are then dried over magnesium sulphate and filtered; the solvent is evaporated off. After purification by chromatography on silica gel (cyclohexane/ethyl acetate: 1/1), the expected product is isolated.
• the product is obtained according to the procedure of Example 1c, using the compound of Example 16b as substrate.
• Example 16c To a solution of the compound of Example 16c (0.067 mmol), dissolved in 20 ml of methanol, there is added 28% aqueous ammonium hydroxide solution (31 ml). The mixture is stirred for 22 hours at 65° C. After evaporating off the solvents, the residue is taken up in a water/ethyl acetate mixture and is then filtered over a frit. The crystals are washed with ethyl acetate, allowing the expected product to be isolated.
• the product is obtained according to the procedure of Example 4, using the compound of Example 16c as substrate.
• the product is obtained according to the procedure of Example 4, using the compound of Example 17 as substrate.
• Step 1 12-(2-O-tosyl- ⁇ -D-glucopyranosyl)-12,13-dihydro-5H-pyrido[2,3-b]-pyrido[3′2′:4,5]pyrrolo[3,2-g]pyrrolo[3,4-e]indole-5,7(6H)-dione
• Example 12 To a solution of the compound of Example 12 (0.17 mmol) in 10 ml of tetrahydrofuran there are added 23.5 mg of potassium carbonate and 1.7 mmol of para-toluenesulphonic acid chloride. The mixture is heated at reflux for 48 hours. After evaporating off the solvent, the residue is taken up in a water/ethyl acetate mixture and is then filtered over a frit. The crystals are successively washed with ethyl acetate and then with methanol, allowing the expected product to be isolated.
• Step 2 12,13-( ⁇ -D-mannopyranosyl)-5H-pyrido[2,3-b]pyrido[3′,2:4′,5]-pyrrolo[3,2-g]pyrrolo[3,4-e]indole-5,7(6H)-dione
• Step 2 To a solution of the compound obtained in Step 1 (0.062 mmol) in 1.6 ml of dimethylformamide there is added 0.62 mmol of sodium azide. The mixture is stirred at 70° C. for 6 days and is then cooled, poured into water and extracted with ethyl acetate. The organic phase is washed with saturated NaHCO 3 solution and then with saturated NaCl solution and is dried over magnesium sulphate. The solvent is evaporated off and the residue is recrystallised, allowing the expected product to be isolated.
• the product is obtained according to the procedure of Example 1a, using the compound of Preparation G as substrate.
• the product is obtained according to the procedure of Example 1b using the compound of Example 22a as substrate.
• the product is obtained according to the procedure of Example 1c, using the compound of Example 22b as substrate.
• the product is obtained according to the procedure of Example 15, using the compound of Example 22c as substrate.
• the product is obtained according to the procedure of Example 16a, using the compound of Preparation H as substrate.
• the product is obtained according to the procedure of Example 16b, using the compound of Example 24a as substrate.
• the product is obtained according to the procedure of Example 16c, using the compound of Example 24b as substrate.
• the product is obtained according to the procedure of Example 17, using the compound of Example 24c as substrate.
• Murine leukaemia L1210 was used in vitro.
• the cells are cultured in RPMI 1640 complete culture medium containing 10% foetal calf serum, 2 mM glutamine, 50 units/ml of penicillin, 50 ⁇ g/ml of streptomycin and 10 mM Hepes, pH: 7.4.
• the cells are distributed on microplates and exposed to the cytotoxic compounds for 4 doubling periods, or 48 hours.
• the number of viable cells is then quantified by means of a colorimetric assay, the Microculture Tetrazolium Assay (J. Carmichael et al., Cancer Res., 47, 936–942, (1987)).
• IC 50 the concentration of cytotoxic agent which inhibits the proliferation of the treated cells by 50%. All the compounds of the invention exhibit good cytotoxicity with respect to this cell line. By way of illustration, the compounds of Examples 4, 5, 9 and 12 all have IC 50 values better than 10 ⁇ 7 M.
• the compounds of the invention were also tested on human cell lines according to the same experimental protocol as that described for murine leukaemia L1210, but with incubation times of 4 days instead of 2 days.
• the compounds of Examples 3, 4, 5, 15, 17 and 19 all have IC 50 values of less than 1 ⁇ M with respect to the following cell lines:neuroblastoma SK-N-MC, epidermoid carcinoma A431 and small cell lung carcinoma H 69.
• L1210 cells are incubated for 21 hours at 37° C. in the presence of various concentrations of test compounds.
• the cells are then fixed by 70% (v/v) ethanol, washed twice in PBS and incubated for 30 minutes at 20° C. in PBS that contains 100 ⁇ g/ml of RNAse and 50 ⁇ g/ml of propidium iodide.
• the results are expressed in terms of the percentage of the cells that accumulate in the G2+M phase after 21 hours, compared with the control (control: 20%).
• the compounds of the invention are especially interesting.
• the compounds of Examples 3, 4 and 5 at a concentration of less than 0.5 ⁇ M, cause accumulation of at least 80% of cells in the G2+M phase after 21 hours.

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